1. Field of the Invention
The present invention is directed to monophasic pharmaceutical compositions comprising a conjugated estrogen and a hydrophilic or lipophilic excipient. The present invention is also directed to kits and applicators comprising the pharmaceutical compositions. The invention is also directed to methods for treating menopausal conditions in a female comprising administering the pharmaceutical compositions.
2. Background of the Invention
Decreased circulating estradiol levels occur with senescence of the ovaries and reduced follicular development, and cause characteristic symptoms at menopause (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000); Beers, M. R. and Berkow, R., eds., “Gynecology and Abstetrics,” in The Merck Manual of Diagnosis and Therapy, 17th Edition, Merck Research Laboratories, Whitehouse Station, N.J., 1942-1944 (1999)). Common symptoms include hot flashes, menstrual irregularities, night sweats, chills, insomnia, paresthesias, palpitations, tachycardia, cold hands and feet, headache, anxiety, dizziness, nervousness, depression, irritability, impaired cognition, diminished libido, fatigue, gastrointestinal symptoms, and atrophic vaginitis (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000); Beers, M. R. and Berkow, R., eds., “Gynecology and Abstetrics,” in The Merck Manual of Diagnosis and Therapy, 17th Edition, Merck Research Laboratories, Whitehouse Station, N.J., 1942-1944 (1999); Semmens, J. P. and Wagner, G., J. Am. Med. Assoc. 248:445-448 (1982); Bachmann, G. A., Maturitas 22 (Suppl.):S1-S5 (1995); Greendale, G. A., and Judd, H. L., J. Am. Geriatr. Soc. 41:426-436 (1993); Nilsson, K., et al., Maturitas 21:51-56 (1995)). Symptoms are frequently severe enough to cause women to seek treatment and may persist for several years during perimenopause and/or post-menopause.
Estrogen deprivation causes profound changes in the genitourinary tract, and up to 40% of postmenopausal women have symptoms associated with these changes (Greendale, G. A., and Judd, H. L., J. Am. Geriatr. Soc. 41:426-436 (1993)). A lack of vaginal lubrication and frequent vaginal infections are experienced by over 50% of post-menopausal women (Rosen, R., et al., J. Sex & Marital Therapy 19:171-188 (1993); Bachmann, G. A., Maturitas 22 (Suppl.):S1-S5 (1995)). The vaginal mucosa and vulvar skin become thinner, the labia flatten and shrink, and the clitoris, uterus, and ovaries decrease in size (Beers, M. R. and Berkow, R., eds., “Gynecology and Abstetrics,” in The Merck Manual of Diagnosis and Therapy, 17th Edition, Merck Research Laboratories, Whitehouse Station, N.J. (1999), pp. 1942-1944). Vaginal pH increases from the normal 3.5-4.0 (which favors lactobacilli) to 6.0-8.0 (which favors pathogenic organisms) (Pandit, L., and Ouslander, J. G., Am. J Med. Sci. 314:228-231 (1997); Semmens, J. P. and Wagner, G., J. Am. Med. Assoc. 248:445-448 (1982)). Decreased pelvic muscle tone leads to urinary frequency, urgency, and incontinence (Bachmann, G. A., Maturitas 22 (Suppl.):S1-S5 (1995)). Endocervical glandular tissue becomes less active and mucus secretion decreases (Bachmann, G. A., Maturitas 22 (Suppl.):S1-S5 (1995)). The vaginal-epithelium becomes dry and atrophic, which causes inflammation, discomfort, itching, and dyspareunia. The vagina becomes less distensible and elastic and is easily traumatized (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000)). Cytologic examination of vaginal mucosa shows an increased proportion of parabasal cells and a decreased proportion of superficial cells; e.g., a calculated Maturation Index score<55 (Pandit, L., and Ouslander, J. G., Am. J. Med. Sci. 314:228-231 (1997); Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000); Nilsson, K., et al., Maturitas 21:51-56 (1995)). Vaginal ultrasonography of the uterine lining will typically demonstrate endometrium thinning to ≦5 mm, signifying decreased estrogen stimulation (Osmers, R., et al., Lancet 335:1569-1571 (1990)).
Estrogen therapy (ET) or hormone therapy (HT), if not contraindicated, is the treatment of choice for postmenopausal women with urogenital atrophy (Willhite, L. A. and O'Connell, M. B., Pharmacotherapy 21:464-480 (2001); Rigg., L. A., Int. J. Fertil. 31:29-34 (1986)). Various forms of HT have been shown to effectively manage menopausal signs and symptoms, including those associated with vaginal atrophy (Cardozo, I., et al., Obstet. Gynocol. 92:722-727 (1988); Beers, M. R. and Berkow, R., eds., “Gynecology and Abstetrics,” in The Merck Manual of Diagnosis and Therapy, 17th Edition, Merck Research Laboratories, Whitehouse Station, N.J., 1942-1944 (1999); Greendale, G. A., and Judd, H. L., J. Am. Geriatr. Soc. 41:426-436 (1993); Semmens, J. P. and Wagner, G., J. Am. Med. Assoc. 248:445-448 (1982); Bachmann, G. A., Maturitas 22 (Suppl.):S1-S5 (1995); Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000); Nilsson, K., et al., Maturitas 21:51-56 (1995); Osmers, R., et al., Lancet 335:1569-1571 (1990); Rigg., L. A., Int. J. Fertil. 31:29-34 (1986); Marx, P., et al., Maturitas 47:47-54 (2004)). Estrogen therapy decreases vaginal pH (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000)), thickens and revascularizes the vaginal epithelium (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000)), increases the number of superficial cells (thereby increasing the Maturation Index) (Pandit, L., and Ouslander, J. G., Am. J. Med. Sci. 314:228-231 (1997)), and rapidly reverses vaginal atrophy (Bachmann, G. A. and Nevadunsky, N. S., Am. Fam. Phys. 61:3090-3096 (2000)).
A number of therapeutic regimens for estrogen replacement therapy are known, although many of these regimens comprise oral or transdermal administration of estrogens. For example, administration of conjugated equine estrogens, estradiol, and estriol vaginal creams has been shown to restore vaginal cytology to a premenopausal state and to improve urogenital atrophy (Willhite, L. A. and O'Connell, M. B., Pharmacotherapy 21:464-480 (2001)). The cyclic administration of conjugated estrogens daily for three weeks followed by one week off has been proposed (PREMARIN® Vaginal Cream package insert, revised Apr. 28, 2004, Wyeth Pharmaceuticals, Inc., Philadelphia, Pa.). However, results of the Women's Health Initiative (WHI) Study led to FDA recommendations that women receiving estrogen therapy be exposed to the lowest effective dose for the shortest duration of treatment (Hulley and Grady, J. Am. Med. Assoc. 291:1769-71 (2004)). Thus, the use of a less frequent dosing regimen for locally administered estrogen replacement therapy has particular appeal.